rs2517951

Variant names:

• chr17-39696844-C-T
• rs2517951
• ENST00000578199.5:c.-18+1663C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000578199.5(ERBB2):​c.-18+1663C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,098 control chromosomes in the GnomAD database, including 23,865 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (23834 hom., cov: 30)
  • Exomes 𝑓: 0.50 (31 hom.)
• Consequence: ERBB2 ENST00000578199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514
• Publications: 14 publications found

Genes affected

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

PGAP3 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-24+1663C>T		intron_variant	Intron 4 of 30		NP_001276865.1
ERBB2	NM_001005862.3	c.-18+1663C>T		intron_variant	Intron 4 of 29		NP_001005862.1
ERBB2	NM_001382782.1	c.-18+1663C>T		intron_variant	Intron 4 of 29		NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+1663C>T		intron_variant	Intron 4 of 17	1		ENSP00000462808.1
ERBB2	ENST00000406381.6	c.-18+1663C>T		intron_variant	Intron 1 of 26	5		ENSP00000385185.2
ERBB2	ENST00000584601.5	c.-69+1663C>T		intron_variant	Intron 4 of 30	2		ENSP00000462438.1
PGAP3	ENST00000584856.1	c.-374G>A		upstream_gene_variant		4		ENSP00000463785.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79555 AN: 151724 Hom.: 23824 Cov.: 30

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.496 AC: 126 AN: 254 Hom.: 31 Cov.: 0 AF XY: 0.549 AC XY: 101 AN XY: 184

African (AFR) AF: 0.167 AC: 1 AN: 6

American (AMR) AF: 0.333 AC: 2 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2 AN: 4

East Asian (EAS) AF: 0.600 AC: 6 AN: 10

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.361 AC: 13 AN: 36

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.542 AC: 91 AN: 168

Other (OTH) AF: 0.438 AC: 7 AN: 16

GnomAD4 genome AF: 0.524 AC: 79580 AN: 151844 Hom.: 23834 Cov.: 30 AF XY: 0.524 AC XY: 38865 AN XY: 74190

African (AFR) AF: 0.228 AC: 9454 AN: 41386

American (AMR) AF: 0.534 AC: 8156 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2380 AN: 3472

East Asian (EAS) AF: 0.396 AC: 2039 AN: 5152

South Asian (SAS) AF: 0.669 AC: 3213 AN: 4804

European-Finnish (FIN) AF: 0.682 AC: 7188 AN: 10534

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45107 AN: 67910

Other (OTH) AF: 0.548 AC: 1156 AN: 2110

Alfa AF: 0.559 Hom.: 5156

Bravo AF: 0.497

Asia WGS AF: 0.563 AC: 1958 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.79
PhyloP100		-0.51
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2517951; hg19: chr17-37853097;